Invasive squamous cell carcinoma is the most common malignant tumor of the upper aerodigestive tract. Despite advances in surgical and radiotherapeutic approaches for therapy, the overall prognosis of oral and head and neck cancer remains poor primarily due to its aggressive invasive capacity, recurrence, and local and distant metastases. Oral squamous cell carcinomas with regional metastasis have a survival rate close to 50%. There is an urgent need to develop novel molecular targets that yield new effective therapeutic approaches. Squamous cell carcinomas present as tightly associated nests of three-dimensional tumor with extensive cell-cell junctional adhesions that permit cell growth and resistance to apoptotic insults. Our findings implicated the involvement of intercellular adhesions in conferring this protection and revealed that cell-cell contacts provide discrete cell survival signaling. The overall goal of this project is to define the mechanisms that regulate growth factor receptor signaling profiles that lead to more aggressive oral SCC cell populations and to identify how complex cellular microenvironmental interrelationships contribute to development of resistance to inhibitors targeting ErbB axis family members. Recent clinical studies have examined the prognostic relevance of overexpressed ErbB3 in HNSCC and report that elevated ErbB3 correlates with metastatic disease and poor overall patient survival. This project focuses specifically on the overriding hypothesis that in oral SCC development, high-density three-dimensional nests of tumor cells promote shifts in specific ErbB family signaling profiles favoring enhanced proliferation and tumor progression. Aim 1 will investigate how the 3D-tumor microenvironment regulates cell growth. Aim 2 will identify the mechanism controlling ErbB receptor profile in tumor foci. Aim 3 will define the importance of HIF-1? induction of ErbB receptor expression in tumor progression. These proposed studies should foster an increased understanding of the evolution of aggressive HNSCC that could be exploited for the future development of novel therapeutic strategies.